The invention relates to treatment of disordered breathing episodes.
Sleep disturbance is a primary reason why many people do not feel rested after a night""s sleep. Sleep disturbance diminishes the productivity and quality of life of individuals who experience it. One class of disorders which disturb sleep is obstructive sleep-disordered breathing, in which loss of upper airway patency prevents or interrupts restful sleep.
Upper airway patency in mammals is modulated by upper airway anatomy and dilatory muscle activity. Reduced activity of these muscles can lead to a narrowing or obstruction of the upper airway, with the result that normal breathing is interfered with or interrupted (Remmers et al., 1978, J. Appl. Physiol. 44:931-938; Strohl et al., 1987, Chest 92:918-920). An episode of interference with or interruption of normal breathing caused by collapse of the upper airway is designated a disordered breathing episode. These are also commonly referred to as apneas, hypopneas, and respiratory effort-related arousals.
There is evidence that certain individuals are anatomically predisposed to disordered breathing episodes, these individuals having upper airway passages which are narrower than those in individuals who do not regularly experienced disordered breathing episodes. In sleep, activity of upper airway dilatory muscles is reduced, and this may cause sleep-disordered breathing episodes.
Obstructive sleep-disordered breathing is prevalent in humans, is associated with significant morbidity and mortality, and is a condition for which there are no well-tolerated, universally-effective pharmacotherapies. It is estimated that twenty million persons in the United States are afflicted with sleep apnea, a less precise term for obstructive sleep-andordered breathing. Sleep apnea is a condition associated with disordered breathing episodes which disturb or interrupt sleep. Thus, the need for an effective treatment or preventative for episodes of disordered breathing is severe.
The physiological or biochemical mechanisms which underlie loss of upper airway patency are not well understood. It is known that apneas tend to be longer and more severe during rapid eye movement (REM) sleep than during other periods of sleep (Findley et al., 1985, Chest 87:432436). Unlike the postural muscle atonia of REM sleep, upper airway muscle atonia is not mediated primarily through a glycinergic post-synaptic inhibition of the relevant motoneurons (Morales et al., 1981, Brain Res. 225:279-295; Soja et al., 1987, Exp. Neurol. 96:178-93; Kubin et al., 1993, Brain Res. 611:300-312). Thus, withdrawal of excitory stimuli from hypoglossal motoneurons during REM sleep likely accounts for much of the suppression of motor activity of upper airway musculature (Kubin et al., 1993, Brain Res. 611:300-312). Microinjection of serotonin into brainstem motor nuclei in vivo results in increased activity of muscles innervated by trigeminal neurons and increased activity of hypoglossal motoneurons (Ribeiro-do-Valle et al., 1991, Brain Res. 550:197-204; Kubin et al., 1992, Neurosci. Lett. 139:243-248). Microinjection of a thyrotropin-releasing hormone (TRH) analog into the hypoglossal nucleus produces a powerful respiratory-related excitation of hypoglossal motoneurons (Magalang et al., 1996, Sleep Res. 25:16). The primary source of both serotonin and TRH for hypoglossal motoneurons is serotonergic neurons within the caudal medullary nuclei raphe obsurus and raphe pallidus, which are two of the raphe nuclei of the mammalian brainstem (Manaker et al., 1993, J. Comp. Neurol. 334:466-476; Hokfelt et al;, 1980, In: Neural Peptides and Neural Communication, Trabucchi, Ed., Raven press, New York, pp. 1-23). The firing rate of these serotonergic neurons is reduced during non-REM sleep. Furthermore, many of these serotonergic neurons cease firing during REM sleep (Heym et al., 1982, Brain Res. 251:259-276).
An animal model of sleep-disordered breathing in humans has been described, namely the English bulldog (Hendricks et al., 1987, J. Appl. Physiol. 63:1344-1350). English bulldogs have significantly narrowed upper airways, daytime hypersomnolence, shortened sleep latencies, and frequent sleep-disordered breathing episodes that are most pronounced during REM sleep (Hendricks et al., 1987, J. Appl. Physiol. 63:1344-1350). Recent studies using this animal model have demonstrated that sleep-disordered breathing episodes occur most frequently in association with the phasic reductions in upper airway dilator muscle activity that occur during REM sleep (Hendricks et al., 1991, Am. Rev. Respir. Dis. 144:1112-1120). Furthermore, normal respiration during waking and sleep in this animal model is associated with augmented upper airway motor activity, just as it is in persons afflicted with obstructive sleep apnea (Hendricks et al., 1993, Am. Rev. Respir. Dis. 148:185-194; Mezzanote et al., 1989, J. Clin. Invest. 89:1571-1579).
Sleep-disordered breathing episodes cause snoring, hypersomnolence, and frequent sleep interruption. Persons who experience such episodes may be less alert than they would be in the absence of such episodes and may not be able to experience restful sleep. Thus, both the productivity and the quality of life of these persons would be greatly increased if their sleep-disordered breathing episodes could be modulated or eliminated. Compositions which have been used to treat sleep apnea have each included one of the following ingredients: the antidepressant protriptyline, the serotonin re-uptake inhibitors fluoxetine and trazadone, the anxiolytic buspirone, and L-tryptophan (Hanzel et al., 1991, Chest 100:416-421; Salazar-Grueso et al., 1988, Ann. Neurol. 23:394-401; Mendelson et al., 1991, J. Clin. Psychopharmacol. 11:71-72; Schmidt, 1983, Bull Eur. Physiopath. Resp. 19:625-629). Administration of these compounds treated sleep apnea in patients with mixed results. The present invention provides improved, and thus more effective, compositions and methods for modulating or eliminating disordered breathing episodes, including episodes of sleep-disordered breathing such as obstructive sleep apnea.
The invention relates to a composition for alleviating or preventing a disordered breathing episode in a mammal. The composition comprises a serotonin re-uptake inhibitor and an agent selected from the group consisting of a serotonin precursor and a serotonin agonist.
In one embodiment of the composition of the invention, the serotonin re-uptake inhibitor is selected from the group consisting of trazadone, fluoxetine, and nefazodone.
In another embodiment of the composition of the invention, the serotonin precursor is selected from the group consisting of L-tryptophan and L-5-hydroxytryptophan.
In yet another embodiment of the composition of the invention, the serotonin re-uptake inhibitor comprises trazadone, the serotonin precursor comprises L-tryptophan, and the ratio, by weight, of L-tryptophan to trazodone is between about 13.3 to 1 and about 13.5 to 1.
In still another embodiment of the composition of the invention, the serotonin agonist is selected from the group consisting of serotonin, 5-CT, and DOI.
In one aspect, the composition of the invention comprises both the serotonin precursor and the serotonin agonist. In another aspect, the composition further comprises a TRH agonist, such as one selected from the group consisting of TRH, montirelin, and CG-3703.
The invention also relates to a kit for alleviating or preventing a disordered breathing episode in a mammal. The kit comprises a serotonin re-uptake inhibitor and an agent selected from the group consisting of a serotonin precursor and a serotonin agonist.
In one embodiment of the kit of the invention, the agent is selected from the group consisting of L-tryptophan, L-5-hydroxytryptophan, serotonin, 5-CT, and DOI and is in a unit dosage form.
In another embodiment of the kit of the invention, the serotonin re-uptake inhibitor is selected from the group consisting of trazadone, fluoxetine, and nefazodone and is in a unit dosage form.
In yet another embodiment of the kit of the invention, the unit dosage form of the agent is an oral unit dosage form and wherein the unit dosage form of the serotonin re-uptake inhibitor is an injectable solution.
In still another embodiment of the kit of the invention, the kit further comprises an instructional material describing administration of the serotonin re-uptake inhibitor and the agent for the purpose of alleviating or preventing a disordered breathing episode in a mammal.
The invention further relates to a method of alleviating a disordered breathing episode in a mammal. This method comprises administering a serotonin re-uptake inhibitor to the mammal and administering an agent to the mammal. The disordered breathing episode is thereby alleviated. The serotonin re-uptake inhibitor is administered in an amount effective to enhance or extend the hypoglossal motoneuron-stimulating effect of endogenous serotonin of the mammal. The agent is selected from the group consisting of a serotonin precursor and a serotonin agonist, and is administered in an amount effective to prevent tachyphylaxis associated with administration to the mammal of the serotonin re-uptake inhibitor.
In one embodiment of this method, the mammal is afflicted with a condition associated with a disordered breathing episode, such as one selected from the group consisting of hypersomnolence, snoring, hypopneas, apneas, obstructive sleep apnea, sleep hypopnea syndrome, upper airway resistance syndrome, and severe snoring conditions associated with arousal from sleep. Preferably the mammal is a human.
In another embodiment of this method, the serotonin re-uptake inhibitor is selected from the group consisting of trazadone, fluoxetine, and nefazodone.
In yet another embodiment of this method, the serotonin precursor is selected from the group consisting of L-tryptophan and L-5-hydroxytryptophan,
In still another embodiment of this method, the serotonin agonist is selected from the group consisting of serotonin, 5-CT, and DOI.
In another embodiment of this method, both the serotonin precursor and the serotonin agonist are administered to the mammal.
In one aspect, this method further comprises administering a TRH agonist to the mammal. The TRH agonist may, for example, be one selected from the group consisting of TRH, montirelin, and CG-3703.
The invention still further relates to a method of preventing a disordered breathing episode in a mammal imminently anticipated to experience a disordered breathing episode. This method comprises administering a serotonin re-uptake inhibitor to the mammal and administering an agent to the mammal. The disordered breathing episode is thereby alleviated. The serotonin re-uptake inhibitor is administered in an amount effective to enhance or extend the hypoglossal motoneuron-stimulating effect of endogenous serotonin of the mammal. The agent is selected from the group consisting of a serotonin precursor and a serotonin agonist and is administered in an amount effective to prevent tachyphylaxis associated with administration to the mammal of the serotonin re-uptake inhibitor.
In one embodiment of this method, the mammal is afflicted with a condition associated with a disordered breathing episode, such as one selected from the group consisting of hypersomnolence, snoring, hypopneas, apneas, obstructive sleep apnea, sleep hypopnea syndrome, upper airway resistance syndrome, and severe snoring conditions associated with arousal from sleep. Preferably, the mammal is a human.
In another embodiment of this method, the serotonin re-uptake inhibitor is selected from the group consisting of trazadone, fluoxetine, and nefazodone.
In yet another embodiment of this method, the serotonin precursor is selected from the group consisting of L-tryptophan and L-5-hydroxytryptophan.
In still another embodiment of this method, the serotonin agonist is selected from the group consisting of serotonin, 5-CT, and DOI.
In another embodiment of this method, both the serotonin precursor and the serotonin agonist are administered to the mammal.
In aspect, this method further comprises administering a TRH agonist to the mammal, such as one selected from the group consisting of TRH, montirelin, and CG-3703.